Tropone derivatives

ABSTRACT

Tropone derivatives substituted with an amino-, thio- or oxy-derivative of oxalic acid or acetic acid are disclosed. In addition, the tropone nucleus can be optionally further substituted. The foregoing compounds are useful for preventing or treating allergic conditions in a mammal. Methods for the preparation and use of the compounds are disclosed.

This is a division of application Ser. No. 697,295, filed June 17, 1976now U.S. Pat. No. 4,066,784.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention related to novel tropone derivatives, to processes fortheir preparation, to methods for using said derivatives, and totherapeutically acceptable salts and compositions of said derivatives.

More specifically, the present invention relates to novel troponederivatives possessing valuable pharmacologic properties. For example,these derivatives are useful for preventing or treating allergicconditions in a mammal at dosages which do not elicit undesirable sideeffects. The combination of these pharmacologic properties renders thetropone derivatives of the invention therapeutically useful.

(B) Description of the Prior Art

A rather large number of reports dealing with tropone derivatives areavailable. The prior art relating to tropones is summarized in variousreviews; for example, see the review by F. Pietra in Chem. Rev., 73, 293(1973). In addition, other tropone derivatives are reported; forinstance, a class of alkyl esters of 5-amidotropoles is described by L.D. Donaruma, Canadian Pat. No. 787,451, issued June 11, 1968; N-troponylamino acid esters are described in the Japanese Pat. No. 24371/63,issued Nov. 15, 1963; and (2-troponylthio)acetic acid is described by T.Nozoe et al., Proc. Japan Acad., 29, 22 (1953).

The tropone derivatives of the present invention are distinguished fromthe prior art compounds by the nature of the substituents on the troponenucleus and by their pharmacologic properties.

SUMMARY OF THE INVENTION

The compounds of this invention are represented by formula I ##STR1## inwhich R¹, R², R³, R⁴, R⁵ and R⁶ are the same or different selected fromthe group consisting of hydrogen; halo; trifluoromethyl; lower alkoxy;lower alkyl; phenyl; hydroxy; phenoxy; mercapto; NR⁷ R⁸ wherein each ofR⁷ and R⁸ is hydrogen or lower alkyl; and a radical of formula Y--CR⁹R¹⁰ --COOR¹¹ wherein Y is O, S or NR¹² wherein R¹² is hydrogen or loweralkyl, R⁹ and R¹⁰ together are oxo and R¹¹ is hydrogen or lower alkyl,or Y is SO or SO₂, R⁹ and R¹⁰ are hydrogen and R¹¹ is hydrogen or loweralkyl; with the proviso that one, two or three of R¹, R², R³, R⁴, R⁵, R⁶must be a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y, R⁹, R¹⁰ andR¹¹ are as defined in each instance herein; and with the additionalproviso that when R¹ and/or R⁴ is a radical of formula Y--CR⁹ R¹⁰--COOR¹¹ wherein Y is NR¹² wherein R¹² is as defined herein, R⁹ and R¹⁰together are oxo and R¹¹ is as defined herein, then at least one of R²,R³, R⁵ and R⁶ must be a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ whereinY, R⁹, R¹⁰ and R¹¹ are as defined in each instance herein.

A preferred group of compounds of this invention is represented byformula I in which R¹, R², R³, R⁴, R⁵ and R⁶ are the same or differentselected from the group consisting of hydrogen or a radical of formulaY--CR⁹ R¹⁰ --COOR¹¹ wherein Y is O, S or NR¹² wherein R¹² is hydrogen orlower alkyl, R⁹ and R¹⁰ together are oxo and R¹¹ is hydrogen or loweralkyl, or Y is SO or SO₂, R⁹ and R¹⁰ are hydrogen and R¹¹ is hydrogen orlower alkyl; with the proviso that one, two or three of R¹, R², R³, R⁴,R⁵ and R⁶ must be a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y,R⁹, R¹⁰ and R¹¹ are as defined in each instance herein; and with theadditional proviso that when R¹ and/or R⁴ is a radical of formula Y--CR⁹R¹⁰ --COOR¹¹ wherein Y is NR¹² wherein R¹² is as defined herein, R⁹ andR¹⁰ together are oxo and R¹¹ is as defined herein, then at least one ofR², R³, R⁵ and R⁶ must be a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹wherein Y, R⁹, R¹⁰ and R¹¹ are as defined in each instance herein.

Another preferred group of compounds of this invention is represented byformula I in which

(a) R¹ is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y is O or S.R⁹ and R¹⁰ together are oxo and R¹¹ is hydrogen or lower alkyl, and R²,R³, R⁴, R⁵ and R⁶ are hydrogen; or

(b) R¹ is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y is SO orSO₂ R⁹ and R¹⁰ are hydrogen and R¹¹ is hydrogen or lower alkyl, and R²,R³, R⁴, R⁵ and R⁶ are hydrogen; or

(c) each of R¹ and R⁶ is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹wherein Y is NR¹² wherein R¹² is hydrogen or lower alkyl, R⁹ and R¹⁰together are oxo and R¹¹ is hydrogen or lower alkyl, and R², R³, R⁴ andR⁵ are hydrogen.

The therapeutically acceptable salts of the compounds of formula I arealso included within the scope of this invention.

The compounds of this invention of formula I are prepared by a processcomprising:

condensing a compound of formula II ##STR2## in which R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷ and R¹⁸ are the same or different selected from the groupconsisting of hydrogen; halo; trifluoromethyl; lower alkoxy; loweralkyl; phenyl; hydroxy; phenoxy; mercapto; NR⁷ R⁸ wherein R⁷ is loweralkyl and R⁸ is hydrogen or lower alkyl; and NHR¹² wherein R¹² ishydrogen or lower alkyl; with the proviso that one, two or three of R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ must be hydroxy, mercapto or NHR¹² whereinR¹² is as defined herein, and with the additional proviso that when R¹³and/or R¹⁶ is NHR¹², then at least one of R¹⁴, R¹⁵, R¹⁷ and R¹⁸ must beNHR¹², hydroxy or mercapto with a compound of formula III

    halogen-CR.sup.9 R.sup.10 --COOR.sup.11                    (III)

in which R⁹ and R¹⁰ are as defined herein, R¹¹ is lower alkyl and thehalogen is bromine, chlorine or iodine in the presence of a protonacceptor to obtain the corresponding compound of formula I in which R¹,R², R³, R⁴, R⁵ and R⁶ are the same or different selected from the groupconsisting of hydrogen; halo; trifluoromethyl; lower alkoxy; loweralkyl; phenyl; hydroxy; phenoxy; NR⁷ R⁸ wherein R⁷ is lower alkyl and R⁸is hydrogen or lower alkyl; and a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹wherein Y is O, S or NR¹² wherein R¹² is as defined herein, R⁹ and R¹⁰together are oxo and R¹¹ is lower alkyl, with the proviso that when R¹and/or R⁴ is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y is NR¹²,R⁹ and R¹⁰ together are oxo and R¹¹ is lower alkyl, then at least one ofR², R³, R⁵ and R⁶ must be a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹wherein Y is O, S or NR¹², R⁹ and R¹⁰ together are oxo and R¹¹ is loweralkyl; and the corresponding intermediate of formula IV ##STR3## inwhich R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are the same or different selectedfrom the group consisting of hydrogen; halo; trifluoromethyl; loweralkoxy; lower alkyl; phenyl; hydroxy; phenoxy; NR⁷ R⁸ wherein R⁷ islower alkyl and R⁸ is hydrogen or lower alkyl; and a radical of formulaY--CR⁹ R¹⁰ --COOR¹¹ wherein Y is S, R⁹ and R¹⁰ are hydrogen and R¹¹ islower alkyl, and oxidizing the intermediate of formula IV to obtain thecorresponding compound of formula I in which R¹, R², R³, R⁴, R⁵ and R⁶are the same or different selected from the group consisting ofhydrogen; halo; trifluoromethyl; lower alkoxy; lower alkyl; phenyl;hydroxy; phenoxy; NR⁷ R⁸ wherein R⁷ is lower alkyl and R⁸ is hydrogen orlower alkyl; and a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y isSO or SO₂, R.sup. 9 and R¹⁰ are hydrogen and R¹¹ is lower alkyl; and ifdesired and required, followed by transformation of the compound offormula I, prepared as described above, to other compounds of formula Iby methods described herein.

In another embodiment of the process of this invention, the compound offormula II in which R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are the same ordifferent selected from the group consisting of hydrogen; halo;trifluoromethyl; lower alkoxy; lower alkyl; phenyl; phenoxy; NR⁷ R⁸wherein each of R⁷ and R⁸ is lower alkyl; with the proviso that at leastone of R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ must be lower alkoxy or halowherein the halo is selected from chlorine, bromine or iodine iscondensed with a compound of formula V

    h--y--cr.sup.9 r.sup.10 --coor.sup.11                      (v)

in which R⁹ and R¹⁰ are hydrogen, R¹¹ is lower alkyl and Y is S in thepresence of a proton acceptor to obtain the corresponding intermediateof formula IV in which R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are the same ordifferent selected from the group consisting of hydrogen;trifluoromethyl; lower alkyl; phenyl; phenoxy; NR⁷ R⁸ wherein each of R⁷and R⁸ is lower alkyl and a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹wherein Y is S, R⁹ and R¹⁰ are hydrogen and R¹¹ is lower alkyl, with theproviso that at least one of R¹⁹, R²⁰, R²¹, R²², R²³ or R²⁴ is theradical of formula Y--CR⁹ R¹⁰ --COOR¹¹ as defined in the last instance,and oxidizing the intermediate of formula IV to obtain the correspondingcompound of formula I in which R¹, R², R³ , R⁴, R⁵ and R⁶ are the sameor different selected from the group consisting of hydrogen;trifluoromethyl; lower alkyl; phenyl; phenoxy; NR⁷ R⁸ wherein each of R⁷and R⁸ is lower alkyl; and a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹wherein Y is SO or SO₂, R⁹ and R¹⁰ are hydrogen and R¹¹ is lower alkyl;and, if desired and required, followed by transformation of the compoundof formula I, prepared as described above, to other compounds of formulaI by methods described herein.

More specifically, the transformation of the compound of formula I,prepared as described above, to other compounds of formula I comprises:

reacting the compound of formula I in which at least one of R¹, R², R³,R⁴, R⁵ and R⁶ is lower alkoxy, chlorine, bromine or iodine with ammoniaor an amine of formula HNR⁷ R⁸ wherein each of R⁷ and R⁸ is hydrogen orlower alkyl to obtain the corresponding compound of formula I in whichthe corresponding R¹, R², R³, R⁴, R⁵ and R⁶ is NR⁷ R⁸ wherein each of R⁷and R⁸ is hydrogen or lower alkyl;

reacting the compound of formula I in which at least one of R¹, R², R³,R⁴, R⁵ and R⁶ is lower alkoxy, chlorine, bromine or iodine with sodiumsulfhydrate to obtain the corresponding compound of formula I in whichthe corresponding R¹, R², R³, R⁴, R⁵ and R⁶ is mercapto; and

hydrolyzing the compound of formula I, prepared as described above, inwhich at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is a radical of formulaY--CR⁹ R¹⁰ --COOR¹¹ wherein R⁹, R¹⁰ and Y are as defined in eachinstance herein and R¹¹ is lower alkyl to obtain the correspondingcompound of formula I in which the corresponding R¹, R², R³, R⁴, R⁵ andR⁶ is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein R⁹, R¹⁰ and Y areas defined herein and R¹¹ is hydrogen.

Another aspect of this invention involves a method for preventing ortreating allergic conditions in a mammal which comprises administeringto said mammal an allergy alleviating effective amount of a compound offormula I, or a therapeutically acceptable salt thereof.

Still another aspect involves a pharmaceutical composition comprising acompound of formula I, or a therapeutically acceptable salt thereof, anda pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates both straight andbranched chain alkyl radicals containing from one to six carbon atomsand includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl and the like.

The term "lower alkoxy" as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to six carbon atomsand includes methoxy, ethoxy, isopropoxy, butoxy, hexanoxy and the like.

The term "halo" as used herein contemplates halogens and includefluorine, chlorine, bromine and iodine, unless stated otherwise.

The term "lower alkanol" as used herein contemplates both straight andbranched chain alkanols containing from one to six carbon atoms andincludes methanol, ethanol, isopropanol, butanol, hexanol and the like.

The acidic compounds of formula I in which R¹, R², R³, R⁴, R⁵ and/or R⁶is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y, R⁹ and R¹⁰ are asdefined herein and R¹¹ is hydrogen form salts with suitabletherapeutically acceptable inorganic and organic bases. These derivedsalts possess the same activity as the parent acid and are includedwithin the scope of this invention. The acid is transformed in excellentyield into the corresponding therapeutically acceptable salts byneutralization of said acid with the appropriate inorganic or organicbase. The salts are administered in the same manner as the parent acidcompounds. Suitable inorganic bases to form these salts include, forexample, the hydroxides, carbonates, bicarbonates or alkoxides of thealkali metals or alkaline earth metals, for example, sodium, potassium,magnesium, calcium and the like. Suitable organic bases include thefollowing amines; lower mono-, di- and trialkylamines, the alkylradicals of which contain up to three carbon atoms, such as methylamine,dimethylamine, trimethylamine, ethylamine, di- and triethylamine,methylethylamine, and the like; mono-, di and trialkanolamines, thealkanol radicals of which contain up to three carbon atoms, for example,mono-, di- and triethanolamine; alkylene-diamines which contain up tosix carbon atoms, such as hexamethylenediamine; cyclic saturated orunsaturated bases containing up to six carbon atoms, such aspyrrolidine, piperidine, morpholine, piperazine and their N-alkyl andN-hydroxyalkyl derivatives, such as N-methyl-morpholine andN-(2-hydroxyethyl)piperidine, as well as pyridine. Furthermore, theremay be mentioned the corresponding quaternary salts, such as thetetraalkyl (for example tetramethyl), alkyl-alkanol (for examplemethyltrimethanol and trimethyl-monoethanol) and cyclic ammonium salts,for example the N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)morpholinium, N,N-dimethylmorpholinium,N-methyl-N-(2-hydroxyethyl)morpholinium, N,N-dimethylpiperidinium salts,which are characterized by having good water-solubility. In principle,however, there can be used all the ammonium salts which arephysiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the acid of formula I in watercontaining at least one equivalent amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. Advantageously,the reaction is performed in a water-miscible, inert organic solvent,for example, methanol, ethanol, dioxane, and the like in the presence ofwater. For example, such use of sodium hydroxide, sodium carbonate orsodium bicarbonate gives a solution of the sodium salt. Evaporation ofthe solution or addition of a water-miscible solvent of a more moderatepolarity, for example, a lower alkanol, for instance, butanol, or alower alkanone, for instance, ethyl methyl ketone, gives the solidinorganic salt if that form is desired.

To produce an amine salt, the acid of formula I is dissolved in asuitable solvent of either moderate or lower polarity, for example,ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least anequivalent amount of the amine corresponding to the desired cation isthen added to that solution. If the resulting salt does not precipitate,it can usually be obtained in solid form by addition of a misciblediluent of low polarity, for example, benzene or petroleum ether, or byevaporation. If the amine is relatively volatile, any excess can easilybe removed by evaporation. It is preferred to use substantiallyequivalent amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid of formula I with an equivalent amount of the correspondingquaternay ammonium hydroxide in water solution, followed by evaporationof the water.

The basic compounds of formula I in which R¹, R², R³, R⁴, R⁵ and/or R⁶is NR⁷ R⁸ wherein R⁷ and R⁸ are as defined herein or a radical offormula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y is NR¹² wherein R¹² is as definedherein, R⁹ and R¹⁰ are hydrogen and R¹¹ is lower alkyl form additionsalts with suitable inorganic and organic acids. These salts possess thesame activities as the parent base compound when administered to amammal and may be utilized in the same manner. Suitable acids to formthese salts include, for example, the common mineral acids, hydrohalic,sulfuric or phosphoric, as well as the organic acids, formic, acetic,maleic, malic, citric, or tartaric acid, or acids which are sparinglysoluble in body fluids and which impart slow-release properties to theirrespective salts such as pamoic or tannic acid or carboxymethylcellulose. The addition salts thus obtained are the functionalequivalent of the parent base compound is respect to their therapeuticuse. Hence, these addition salts are included within the scope of thisinvention and are limited only by the requirement that the acidsemployed in forming the salts be therapeutically acceptable.

Also included within the scope of this invention are the isomers of thecompounds of formula I resulting from the asymmetric centers containedtherein.

The tautomeric forms of the compounds of formula I in which R¹, R², R³,R⁴, R⁵ and/or R⁶ is hydroxy, resulting from the keto-enol equilibriumcontained therein, are also included within the scope of this invention.

Anti-allergic Activity

The compounds of this invention of formula I, or therapeuticallyacceptable salts thereof, are useful in the prevention or treatment ofallergic reactions in a mammal upon oral or parenteral administration.

More specifically, the compounds of this invention are useful for theprophylactic treatment as well as for the management of anaphylaticreactions and atopic allergic manifestations, for example, bronchialasthma, hay fever, allergic rhinitis, allergic conjunctivitis, foodallergies, urticaria and the like, in a sensitized mammal.

More specifically exemplified, the compounds of this invention areeffective anti-allergic agents when tested using the passive cutaneousanaphylaxis (PCA) method, described by I. Mota, Immunology, 7, 681(1964). The anti-allergic activity of a given compound is measured inrats by its ability to inhibit the increase in vascular permeability atthe site of injection of rat immunoglobulin E (IgE) followed by i.v.administration of the specific antigen. Evans blue is injected i.v. atthe same time as the specific antigen and the size of the wheal or ofthe area infiltrated with Evans blue is measured and compared with thatof untreated controls. An effective anti-allergic agent will prevent orinhibit the release of inflammatory mediators (mainly serotonin andhistamine from the mast cells) which causes an increase in vascularpermeability and thus an infiltration of Evans blue surrounding the siteof injection of IgE.

The anti-allergic activity of the compounds of formula I is demonstratedby the reduction of the wheal size of sensitized skin tissue compared tothat of control animals. A comparison of the anti-allergic activity of astandard compound, such as disodium cromoglycate, indicates that thecompounds of this invention function in the same manner as disodiumcromoglycate by blocking the release of mediators from the mast cellsresponsible for the allergic reaction.

When the compounds of formula I of this invention are used forsuppressing allergic manifestations of anaphylatic reactions and atopicimmediate hypersenitivity in a mammal, they are used alone or incombination with pharmacologically acceptable carriers, the proportionof which is determined by the solubility and the chemical nature of thecompound, chosen route of administration and standard biologicalpractice. For example, they are administered parenterally by injection;orally; by the nasal route, for instance, as drops or aerosol; byinhalation from an aerosol; or as a suppository.

In addition, the compounds of this invention can be administered inconjunction with common anti-allegics, for example, known compoundseffecting anti-histaminic, analgesic, central nervous system depressant,anti-hypertensive, immunosuppressive, anti-bradykinin, anti-serotonin orendocrinological responses.

Therapeutic compositions containing the compounds of this invention areeffective anti-allergic agents for preparing or relieving atopicallergic manifestations at dosages of 0.1 mg to 100 mg/kg body weightwhen administered parenterally to a mammal. For administration to amammal by parenteral injection it is preferred to use the compounds offormula I in solution in a sterile aqueous vehicle which may alsocontain other solutes such as buffers or preservatives, as well assufficient quantities of pharmaceutically acceptable salts or of glucoseto make the solution isotonic.

A number of the compounds of this invention of formula I are useful inthe management of allergic reactions when administered orally at dosagesof 0.5 mg to 500 mg/kg body weight to a sensitized mammal. For example,the representative compound of formula I,[[3-[N-(2-ethoxy-1,2-dioxoethyl)-N-methylamino]-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-aceticacid ethyl ester (see Example 3) is an effective anti-allergic agentwhen administered orally at dosages of 30 mg to 100 mg/kg body weight.

When the compounds of this invention are employed as anti-allergicagents in mammals, e.g. rats, the orally effective, anti-allergicamounts of the compounds are administered to the mammal, either alone orcombined with pharmaceutically acceptable excipients in a dosage form,i.e. capsule or tablet, or the compounds are administered orally in theform of solutions or suspensions.

The tablet compositions contain the active ingredient in admixture withnon-toxic pharmaceutical excipients known to be suitable in themanufacture of tablets. Suitable pharmaceutical excipients are, forexample, starch, milk sugar, certain types of clay and so forth. Thetablets may be uncoated or they may be coated by known techniques so asto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period.

The aqueous suspensions of the invention contain the active ingredientin admixture with one or more non-toxic pharmaceutical excipients knownto be suitable in the manufacture of aqueous suspensions. Suitableexcipients are, for example, methylcellulose, sodium alginate, gumacacia, lecithin and so forth. The aqueous suspensions may also containone or more preservatives, one or more coloring agents, one or moreflavoring agents and one or more sweetening agents.

Non-aqueous suspensions can be formulated by suspending the activeingredient in a vegetable oil, for example, arachis oil, olive oil,sesame oil, or coconut oil, or in a mineral oil, for example liquidparaffin, and the suspension may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. These compositions can alsocontain a sweetening agent, a flavoring agent and an anti-oxidant.

The compounds of formula I can also be administered as nasal powders orinsufflations. For such purpose the compounds are administered in finelydivided solid form together with a pharmaceutically acceptable solidcarrier, for example, a finely divided polyethylene glycol ("Carbowax1540") or finely divided lactose. Such compositions may also containother excipients in finely divided solid form, for instancepreservatives, buffers, or surface active agents.

When administering the compounds of this invention by inhalation from anaerosol, the compound of formula I is dissolved in water or ethanol andmixed with a volatile propellant, for example, dichlorotetrafluoroethaneand dichlorodifluoromethane, and placed in a pressurized containerhaving a metering valve to release a predetermined amount of material.

The dosage of the compounds of this invention will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstance is reached. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects, and preferably at alevel that is in a range of from about 0.1 mg to about 500 mg perkilogram body weight, although as aforementioned variations will occur.However, a dosage level that is in the range of from about 0.5 mg toabout 200 mg per kilogram body weight is most desirably employed inorder to achieve effective results.

PROCESSES

Useful and practical starting materials for the preparation of thecompounds of this invention of formula I are the tropone derivatives offormula II ##STR4## in which R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are asdefined herein.

The tropone derivatives of formula II suitable as starting materials aredescribed in a number of reports, for example, see the recent review ontropone derivatives, their preparation and their interconversions by F.Pietra, supra. Thus, the tropone derivatives suitable as startingmaterials are either known or they can be prepared by conventionalmeans.

The compounds of this invention of formula I are prepared by thefollowing processes.

In practicing the condensation of the compound of formula II with thecompound of formula III, as noted above, one to ten molar equivalents,preferably one to three molar equivalents, of the compound of formulaIII are used. The reaction medium for the condensation is preferably aninert solvent. Suitable solvents include benzene, toluene, chloroform,methylene chloride, lower alkyl ketones (i.e. 2-propanone, 2-butanoneand 3-pentanone) and the like. However, if the reactants are mutuallysoluble, the solvent can be omitted without deleterious effects.

The preferred proton acceptors include the organic bases or amines, forinstance, triethylamine, pyridine, N-ethylmorpholine,1,5-diazabicyclo(3.4.0)-nonene-5 and the like, as well as the inorganicbases, preferably the alkali metal hydroxides, carbonates, hydrides,amides and alkoxides, for example, sodium ethoxide sodium hydroxide,potassium hydroxide, potassium carbonate, sodium methoxide and the like.The choice of the particular proton acceptor depends upon the reactionconditions as well as the nature of the particular condensation. Forexample, the preferred proton acceptors employed for the preparation ofthe compounds of formula I in which R¹, R², R³, R⁴, R⁵ and/or R⁶ isY--CR⁹ R¹⁰ --COOR¹¹ wherein Y is O are the strong inorganic bases, forinstance the alkali metal alkoxides, hydrides and amides, preferably,sodium ethoxide, sodium methoxide, sodium amide, potassium t-butoxideand the like. In the latter condensation the preferred amount of thestrong inorganic base is about 1.0 to 1.3 molar equivalents. For thepreparation of the compounds of formula I in which R¹, R², R³, R⁴ , R⁵and/or R⁶ is Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y is S or NR¹² the preferredproton acceptors employed are the organic bases or amines. The amount ofthe organic base can vary from one molar equivalent to a large molarexcess. When a large molar excess of an organic base is used, theorganic base can also serve as the solvent for the condensation.

The duration and temperature of the condensation are not critical;however, the preferred time is from about ten minutes to about two daysand the temperature can range from about -10° C. to about 100° C. or theboiling point of the reaction mixture. The compounds of formula I areseparated from the reaction mixture by conventional means, for example,evaporation, filtration, extraction, chromatography and/orcrystallization.

In another embodiment of the process of this invention, the compound offormula II is condensed with the compound of formula V, as noted above.The required amount of the compound of formula V is from one to tenmolar equivalents, preferably one to three molar equivalents.

Suitable solvents, reaction conditions and proton acceptors, preferablyorganic bases for the latter condensation can be selected from thosedescribed for the former condensation of the compound of formula II andthe compound of formula III.

The compounds of formula I, and the intermediates of formula IV,obtained from the above described condensations, can be further reactedto obtain other compounds of formula I by methods described hereinafter.

For instance, the above described compound of formula IV in which atleast one of R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ is a radical of formulaY--CR⁹ R¹⁰ --COOR¹¹ wherein R⁹ and R¹⁰ are hydrogen, R¹¹ is lower alkyland Y is S is oxidized with substantially one molar equivalent of anoxidizing agent, preferably an organic peracid, for example,meta-chloroperbenzoic acid, perbenzoic acid and the like, or hydrogenperoxide, to obtain the corresponding compound of formula I in which thecorresponding R¹, R², R³, R⁴, R⁵ and R⁶ is a radical of formula Y--CR⁹R¹⁰ --COOR¹¹ wherein R⁹ and R¹⁰ are hydrogen and R¹¹ is lower alkyl andY is SO. In the same manner, the use of substantially two to five molarequivalents of the oxidizing agent gives the corresponding compound offormula I in which the corresponding R¹, R², R³, R⁴, R⁵ and R⁶ is aradical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein R⁹, R¹⁰ and R¹¹ are asdefined immediately above and Y is SO₂. The above oxidations arepreferably effected in an inert organic solvent, for example ahaloalkane, i.e., chloroform, methylene chloride, trichloroethane andthe like, at a temperature ranging from about -10° C. to about 60° C.for about ten minutes to above five hours.

In some cases it is convenient and preferable to prepare a specificcompound of formula I by the transformation of another compound offormula I. Examples of such interconversions of the compound of formulaI are described hereinafter.

The compound of formula I, prepared as described above, in which atleast one of R¹, R², R³, R⁴, R⁵ and R⁶ is a radical of formula Y--CR⁹R¹⁰ --COOR¹¹ wherein R⁹, R¹⁰ and Y are as described herein and R¹¹ islower alkyl can be hydrolyzed to obtain the corresponding acidiccompound of formula I in which the corresponding R¹, R², R³, R⁴, R⁵ andR⁶ is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein R⁹, R¹⁰ and Y areas defined herein and R¹¹ is hydrogen. The preferred method ofhydrolysis comprises the use of 0.1 to 2.0 molar equivalents, preferably0.5 to 1.0 molar equivalents, of a mild alkali, for example a suitablemild alkali selected from the bicarbonates and acetates of sodium orpotassium, in an inert solvent, for instance, water, a lower alkanol(i.e. methanol or ethanol) or mixtures thereof, at a temperature ofabout 20° C. to 120° C. for about one to ten hours. Acidification of thereaction mixture with a dilute mineral acid, such as hydrochloric acid,sulfuric acid, phosphoric acid and the like, gives the correspondingacidic compound of formula I.

The acidic compound of formula I described above (i.e. R¹¹ is hydrogen)is readily esterified to obtain the corresponding ester of formula I(i.e., R¹¹ is lower alkyl). Suitable esterification conditions include avariety of methods; for example, ester exchange, treatment withdiazomethane, or conversion of the acid to the corresponding activatedcarbonyl (i.e., acid halide, anhydride, succinimido, imidazolide and thelike) followed by treatment of the latter with an appropriate loweralkanol, see also, L. F. Fieser and M. Fieser, "Advanced OrganicChemistry," Reinhold Publishing Corporation, New York 1961, pp. 370-381.

A preferred and convenient method of esterification comprises dissolvingthe acidic compound of formula I in an inert solvent, preferablydimethylsulfoxide, in the presence of one to ten molar equivalents of amild base, for example, sodium or potassium carbonate. One to threemolar equivalents of a lower alkyl bromide or chloride is added and thesolution is maintained at a temperature of about 20° C. to 100° C.,preferably at about 40° C. to 80° C., for about 30 minutes to fivehours.

The compound of formula I in which at least one of R¹, R², R³, R⁴, R⁵and R⁶ is hydroxy can be alkylated to obtain the corresponding compoundof formula I in which the corresponding R¹, R², R³, R⁴, R⁵ and R⁶ isalkoxy. The alkylation is conveniently carried out by reacting thehydroxy compound with one to five molar equivalents of a di(lower)alkylsulfate, for example dimethyl or diethyl sulfate, in the presence of oneto five molar equivalents of a mild alkali, for instance sodium orpotassium carbonate, in an inert solvent, for example, a lower alkylketone, preferably 2-butanone, 2-propanone and the like. The alkylationis conducted at a temperature from about 30° C. to the boiling point ofthe reaction mixture for about 30 minutes to ten hours.

A useful alternative method of alkylation comprises reacting the hydroxycompound of formula I with an excess of a diazoalkane, for instancediazoethane and the like, in an inert solvent, e.g. diethyl ether ormethanol.

The compound of formula I in which at least one of R¹, R², R³, R⁴, R⁵and R⁶ is lower alkoxy, chlorine, bromine or iodine can be reacted witha molar excess of ammonia or an amine of formula HNR⁷ R⁸ in which R⁷ andR⁸ are as defined herein to obtain the corresponding compound of formulaI in which at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is NR⁷ R⁸ whereinR⁷ and R⁸ are as defined herein. A suitable solvent for the reaction canbe selected from the amine, water and a lower alkanol (i.e. methanol,ethanol and the like). Suitable conditions for the reaction are atemperature of from about -50° C. to about 100° C., preferably 0° C. to100° C., for about ten minutes to 12 hours. If the temperature necessaryfor the reaction is above the boiling point of the reaction mixture, thereaction can be conducted at the desired temperature in a sealedpressure vessel without deleterious effects.

Similarly the compound of formula I in which at least one of R¹, R², R³,R⁴, R⁵ and R⁶ is lower alkoxy, chlorine, bromine or iodine can bereacted with sodium sulfhydrate in an inert solvent, preferably a loweralkanol, i.e. methanol or ethanol, to obtain the corresponding compoundof formula I in which the corresponding R¹, R², R³, R⁴, R⁵ and R⁶ ismercapto. This reaction is preferably carried out at a temperature offrom about -70° C. to about 30° C. for one to ten hours.

The above described processes can be followed to prepare other compoundsof formula I in which R¹ and R², R² and R³, R³ and R⁴, R⁴ and R⁵ or R⁵and R⁶ are joined together with a chain selected from the groupconsisting of --CH═CH--CH═CH--, --C═CH--N═CH-- and --(CH₂)_(n) --wherein n is an integer from 1 to 10 and R³, R⁴, R⁵ and R⁶ ; R¹, R⁴, R⁵and R⁶ ; R¹, R², R⁵ and R⁶, R¹, R², R³ and R⁶ or R¹, R², R³ and R⁴,respectively, are as defined herein.

It should be understood that the invention as disclosed herein wouldalso include compounds of formula I in which R¹, R², R³, R⁴, R⁵ and R⁶are the same or different selected from the group consisting ofhydrogen; halo; trifluoromethyl; lower alkoxy; lower alkyl; phenyl;hydroxy; phenoxy; mercapto; NR⁷ R⁸ wherein each of R⁷ and R⁸ is hydrogenor lower alkyl; and a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Yis O, S or NR¹² wherein R¹² is hydrogen or lower alkyl, R⁹ and R¹⁰together are oxo and R¹¹ is hydrogen or lower alkyl, or Y is SO or SO₂,R⁹ and R¹⁰ are hydrogen and R¹¹ is hydrogen or lower alkyl; with theproviso that one, two or three of R¹, R², R³, R⁴, R⁵ and R⁶ must be aradical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y, R⁹, R¹⁰ and R¹¹ are asdefined herein; and with the additional proviso when one of R¹ or R⁴ isa radical of the formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y is NR¹² whereinR¹² is as defined herein, R⁹ and R¹⁰ together are oxo and R¹¹ is asdefined herein, then R⁴ or R¹ respectively is a radical of the formulaY--CR⁹ R¹⁰ --COOR¹¹ wherein Y is O or S, R⁹ and R¹⁰ together are oxygenand R¹¹ is hydrogen or lower alkyl, or Y is SO or SO₂, R⁹ and R¹⁰ arehydrogen and R¹¹ is hydrogen or lower alkyl and R², R³, R⁵ and R⁶ are asdefined herein.

The following examples illustrate further this invention.

EXAMPLE 1 2-Mercapto-2,4,6-cycloheptatrien-1-one

A solution of 2-chloro-2,4,6-cycloheptatrien-1-one [2.82 g, described byT. Nozoe et al., Proc. Japan Acad., 28, 483 (1952)] in ethanol (20 ml)is added dropwise to a suspension, cooled to -70° C., of sodiumsulfhydrate (2.2 g) in ethanol (20 ml). The mixture is stirred at -70°C. for two hours, allowed to warm to room temperature and stirred atroom temperature for one hour. The mixture is filtered and the filtrateis evaporated. The residue is suspended in water, the mixture isacidified to pH 2 with 10% hydrochloric acid and extracted with ethylacetate. The organic extract is dried and evaporated. The residue isdissolved in benzene and subjected to chromatography on silica gel. Theeluates are evaporated to give the title compound, mp 55° C.

EXAMPLE 2 [(2-Oxo-3,5,7-cycloheptatrien-1-yl)thio]oxo-acetic Acid EthylEster I (R¹ =S--CO--COOC₂ H₅ ; R², R³, R⁴, R⁵, and R⁶ =H)

A solution of ethyl oxalyl chloride (0.58 ml) in methylene chloride (4ml) is added to a solution of 2-mercapto-2,4,6-cycloheptatrien-1-one(0.584 g described in Example 1) and triethylamine (0.66 ml) inmethylene chloride (5 ml) and the mixture is stirred at room temperaturefor 30 minutes. The reaction mixture is diluted with methylene chloride,washed with water, dried and evaporated. The residue is suspended inmethanol, filtered and the filtrate is evaporated to give the titlecompound; nmr (CDCl₃) δ1.4 (t, 3H), 4.4 (q, 2H), 7.15 (m, 4H) and 7.85(M, 1H).

In the same manner but replacing ethyl oxalyl chloride with anequivalent amount of methyl oxalyl chloride, the methyl ester of thetitle compound is obtained.

By following serially the procedures of Examples 1 and 2 but replacing2-mercapto-2,4,6-cycloheptatrien-1-one with an equivalent amount of5-mercapto-7H-benzocyclohepten-7-one,9-amino-7H-cyclohepta[c]pyridin-7-one,5-mercapto-3H-6,7-dihydrocyclobutacyclohepten-3-one,1-ethylamino-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one and5-mercapto-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one,the following compounds are obtained respectively:](7-oxo-7H-benzocyclohepten-5-yl)thio]oxoacetic acid ethyl ester (I; R¹,R⁵, and R⁶ =H; R² =S--CO--COOC₂ H₅ ; and R³ and R⁴ together form a--CH═CH--CH═CH-- chain),[(7-oxo-7H-cyclohepta[c]pyridin-9-yl)-amino]oxo-acetic acid ethyl ester(I; R¹, R⁵ and R⁶ =H; R² =NC₂ H₅ --CO--COOC₂ H₅ ; and R³ and R⁴ togetherform a --CH═CH--N═CH-- chain).[(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-5-yl)thio]oxo-acetic acidethyl ester (I; R¹, R⁵ and R⁶ =H; R² =S--CO--COOC₂ H₅ ; and R³ and R⁴together form a --CH₂ CH₂ -- chain),[N-(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)ethylamino]oxo-aceticacid ethyl ester (I; R¹, R² and R⁶ =H; R³ and R⁴ together form a--(CH₂)₆ chain; and R⁵ =NC₂ H₅ --CO--COOC₂ H₅) and[(3-oxo-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-5-yl)thio]oxoacetic acid ethyl ester (I; R¹, R⁵ and R⁶ =H; R²=S--CO--COOC₂ H₅ ; and R³ and R⁴ together form a --(CH₂)₈ -- chain).

EXAMPLE 3[[3-[N-(2-Ethoxy-1,2-dioxoethyl)-N-methylamino]-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-aceticAcid Ethyl Ester; I; (R¹ =NH--CO--COOC₂ H₅ ; R², R³, R⁴ and R⁵ =H and R⁶=N(CH₃)--CO--COOC₂ H₅)

A mixture of2-hydroxy-3-[[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one[14.5 g, described by Y. Kitahara, Science Repts. Tohoku Univ. Ser. 1,40, 83 (1956)] dimethyl sulfate (12.5 g), potassium carbonate (12.5 g)and 2-butanone (145 ml) is heated at reflux for one hour. The mixture isfiltered and the filtrate is evaporated. The residue is subjected tochromatography on silica gel using hexane-ethyl acetate (1:3). Theeluates are concentrated to obtain crystals of2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one,mp 94.5° C.

A solution of the latter compound (4.0 g) in methanol (40 ml) is cooledto -25° C. and saturated with ammonia gas. The solution in a pressurebottle is heated at 80° C. for four hours and cooled to -70° C. Thebottle is opened and the solution evaporated to give2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one,mp 221°-222° C.

A solution of the latter compound (2.53 g) in conc. sulfuric acid (25ml) is heated at 70° C. for one hour and added to ice. The ice-mixtureis neutralized with sat. sodium carbonate solution and extracted withchloroform. The organic extract is dried over sodium sulfate andevaporated to give 2-amino-7-methylamino-2,4,6-cycloheptatrien-1-one.

A solution of ethyl oxalyl chloride (2.46 g) in methylene chloride (10ml) is added dropwise to a solution of2-amino-7-methylamino-2,4,6-cycloheptatrien-1-one (1.32 g) andtriethylamine (1.95 g) in methylene chloride (15 ml). The mixture isheated at reflux for 3 hours, washed with water, dried over sodiumsulfate and evaporated. The residue is subjected to chromatography onsilica gel using acetone-hexane (3:7) and the eluates are evaporated togive the title compound, nmr (trifluoroacetic acid) δ 1.5 (m, 6H), 3.45(s, 3H), 4.55 (m, 4H) and 7.6-9.2 ppm (m, 4H).

By following a procedure selected from Example 2 or 3 using theappropriate starting material of formula II and the appropriate compoundof formula III, such as methyl or ethyl oxalyl chloride, other compoundsof formula I in which at least one of R¹, R², R³, R⁴, R⁵ and R⁶ isY--CR⁹ R¹⁰ --COOR¹¹ wherein Y is S or NR¹², R⁹ and R¹⁰ together are oxoand R¹¹ is methyl or ethyl are obtained. Examples of the lattercompounds of formula I are listed as products in Table I together withthe appropriate starting material of formula II used for the preparationof the compound of formula I.

    __________________________________________________________________________    STARTING MATERIAL OF FORMULA 11                                               EX. R.sup.1                                                                           R.sup.2                                                                            R.sup.3                                                                             R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                           PRODUCT                                        __________________________________________________________________________    4   CH.sub.3                                                                          Br   H     H   NH.sub.2                                                                          H   [(5-bromo-4-methyl-3-oxo-1,4,6-cycloheptatr                                   ien-1-yl)amino]-                                                              oxo-acetic acid ethyl ester                    5   H   NH.sub.2                                                                           OC.sub.6 H.sub.5                                                                    H   H   l   [(4-iodo-3-oxo-7-phenoxy-1,4,6-cycloheptatr                                   ien-l-yl)amino]-                                                              oxo-acetic acid methyl ester                   6   H   CH.sub.3                                                                           NH(C.sub.3 H.sub.7)                                                                 H   NH.sub.2                                                                          H   [[[6-[N-(2-methoxy-1,2-dioxoethyl)methylami    5-methyl-1,4,6-                no]                                                                           cycloheptatrien-l-yl]amino]oxo-acetic acid                                    ethyl ester                                    7   CF.sub.3                                                                          NH.sub.2                                                                           H     H   C.sub.3 H.sub.7                                                                   H   [(3-oxo-5-propyl-2-trifluoromethyl-1,4,6-cy                                   cloheptatrien-l-                                                              yl)amino]oxo-acetic acid ethyl ester           8   H   Br   H     SH  H   SH  2,2'-[(4-bromo-2-oxo-3,5,7-cycloheptatrien-                                   l-yl)bis(thio)]-                                                              bis[2-oxo-acetic acid]diethyl ester            9   H   N(CH.sub.3).sub.2                                                                  Cl    H   NH.sub.2                                                                          H   [(6-chloro-5-dimethylamino-3-oxo-1,4,6-cycl                                   oheptatrien-l-                                                                yl)amino]oxo-acetic acid ethyl ester           10  SH  H    H     CF.sub.3                                                                          H   C.sub.6 H.sub.13                                                                  [(3-hexyl-2-oxo-6-trfluoromethyl-3,5,7-cycl                                   oheptatrian-1-                                                                yl)thio]oxo-acetic acid methyl ester           11  NH.sub.2                                                                          H    H     C.sub.2 H.sub.5                                                                   H   NH.sub.2                                                                          2,2'-[(5-ethyl-2-oxo-3,5,7-cycloheptatrien-                                   l-yl)diimino]-                                                                bis[2-oxo-acetic acid]dimethyl ester           12  H   OCH.sub.3                                                                          H     C.sub.6 H.sub.5                                                                   SH  H   [(5-methoxy-7-phenyl-3-oxo-1,4,6-cyclohepta                                   trien-1-                                                                      yl)thio]oxo-acetic acid ethyl ester                                           -13 NH.sub.2 H NH.sub.2 H H NH.sub.2 2,2',2                                   "[(2-oxo-3,5,7-cycloheptatriene-1,3,6-triyl                                   )-                                                                            triimino]tris[2-oxo-acetic acid]triethyl                                      ester                                          14  H   H    SH    C.sub.3 H.sub.7                                                                   H   OC.sub.6 H.sub.5                                                                  [(4-oxo-5-phenoxy-7-propyl-2,5,7-cyclohepta                                   trien-1-yl)thio]-                                                             oxo-acetic acid ethyl ester                    15  H   Br   N(C.sub.2 H.sub.5).sub.2                                                            SH  H   Br  [(3,6-dibromo-7-diethylamino-4-oxo-2,5,7-cy                                   cloheptatrien-                                                                1-yl)thio]oxo-acetic acid ethyl ester          16  SH  H    CF.sub.3                                                                            H   C.sub.5 H.sub.11                                                                  H   [(2-oxo-4-pentyl-6-trifluoromethyl-3,5,7-cy                                   cloheptatrien-1-                                                              yl)thio]oxo-acetic acid methyl ester           17  SH  H    H     H   OC.sub.3 H.sub.7                                                                  NH.sub.2                                                                          [[3-[(2-ethoxy-1,2-dioxoethyl)thio]-7-propo                                   xy-3,5,7-cyclo-                                                               heptatrien-1-yl]amino]oxo-acetic acid                                         ethyl ester                                    18  OC.sub.6 H.sub.5                                                                  H    SH    H   H   CF.sub.3                                                                          [(5-oxo-4-phenoxy-6-trifluoromethyl-1,3,6-c                                   ycloheptatrien-                                                               1-yl)thio]oxo-acetic acid methyl ester         19  H   H    H     NH.sub.2                                                                          H   NH.sub.2                                                                          2,2'-[(2-oxo-3,5,7-cycloheptatriene-1,6-diy                                   l)diimino]bis-                                                                [2-oxo-acetic acid]diethyl ester               20  H   NHC.sub.3 H.sub.7                                                                  H     I   OH  H   [N-(4-(hydroxy-3-iodo-6-oxo-2,4,7-cyclohept                                   atrien-1-yl)-N-                                                               propylamino]oxo-acetic acid ethyl ester        21  OH  H    N(C.sub.2 H.sub.5).sub.2                                                            H   SH  H   [(3-diethylamino-5-hydroxy-6-oxo-2,4,7-cycl                                   oheptatrien-1-                                                                yl)thio]oxo-acetic acid ethyl                  __________________________________________________________________________                                   ester                                      

EXAMPLE 22 [(2-Oxo-3,5,7-cycloheptatrien-1-yl)oxy]oxo-acetic Acid EthylEster I (R¹ =O--CO--COOC₂ H₅ ; R², R³, R⁴, R⁵ and R⁶ =H)

To a suspension of the sodium salt (4.27 g) of2-hydroxy-2,4,6-cycloheptatrien-1-one (prepared from2-hydroxy-2,4,6-cycloheptatrien-1-one described by H. C. Stevens et al.,Jour. Org. Chem., 36, 2780 (1971) and sodium ethoxide 1:1 equivalents)in benzene (10 ml) is added a solution of ethyl oxalyl chloride (3.3 ml)in dry benzene (15 ml). The mixture is stirred at room temperature for1.5 hours, diluted with ether and filtered. The filtrate is flushedtwice with benzene and dried under reduced pressure to give the titlecompound as an oil; nmr (CDCl₃) δ 1.35 (t, 3H), 4.39 (q, 2H) and 7.25(m, 5H).

In the same manner but replacing sodium ethoxide with an equivalentamount of sodium methoxide, sodium amide or potassium t-butoxide, thetitle compound is obtained.

In the same manner using the appropriate compound of formula III andreplacing 2-hydroxy-2,4,6-cycloheptatrien-1-one with an equivalentamount of 5-hydroxy-7H-benzocyclohepten-7-one,6-hydroxy-7H-cyclohepta[c]pyridin-7-one,2-hydroxy-3H-6,7-dihydrocyclobutacyclohepten-3-one,1-hydroxy-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one, and2-hydroxy-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one,the following compounds are obtained respectively:[(7H-7-oxobenzocyclohepten-6-yl)oxy]oxo-acetic acid methyl ester (I; R¹,R⁵ and R⁶ =H, R³ and R⁴ together form a --CH═CH--CH═CH-- chain and R²=O--CO--COOCH₃), [(7-oxo-7H-cyclohepta[c]pyridin-6-yl)oxy]oxo-aceticacid ethyl ester (l; R¹, R² and R⁵ =H, R³ and R⁴ together form a --CH₂═CH₂ --N═CH-- chain and R⁶ =O--CO--COOC₂ H₅),[(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-2-yl)oxy]oxo-acetic acidethyl ester (l; R², R⁵ and R⁶ 'H, R³ and R₄ together form a --CH₂ --CH₂-- chain and R¹ =O--CO--COOC₂ H₅),[(3-oxo-3H-6,7,9,10,11-hexahydrocycloheptacyclooten-1-yl)oxy]oxo-aceticacid ethyl ester (l; R¹, R² and R⁶ =H, R³ and R⁴ together form a--(CH₂)₆ -- chain and R⁵ =O--CO--COOC₂ H₅) and[(3H-6,7,8,9,10,11,12,13-octahydro-3-oxocycloheptacyclodecen-2-yl)oxy]oxo-aceticacid methyl ester (l; R¹, R² and R⁵ =H, R³ and R⁴ together form a--(CH₂)₈ -- chain and R⁶ =O--CO--COOCH₃).

By following the procedure of Example 22 using the appropriate startingmaterial of formula II in which at least one of R¹, R², R³, R⁴, R⁵ andR⁶ is hydroxy and the appropriate compound of formula III, such asmethyl or ethyl oxalyl chloride, other compounds of formula I in whichat least one of R¹, R², R³, R⁴, R⁵ and R⁶ is Y--CR⁹ R¹⁰ --COOR¹¹ whereinY is O, R⁹ and R¹⁰ together are oxo and R¹¹ is methyl or ethyl areobtained. Examples of the latter compounds of formula I are listed asproducts in Table II together with the appropriate starting material offormula II used for the preparation of the compound of formula I.

                                      TABLE II                                    __________________________________________________________________________    STARTING MATERIAL OF FORMULA II                                               Ex.                                                                              R.sup.1                                                                          R.sup.2                                                                            R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                           PRODUCT                                         __________________________________________________________________________    23 CH.sub.3                                                                         H    Br   H    H    OH  [(5-bromo-3-methyl-2-oxo-3,5,7-cycloheptatri                                  en-1-yl)oxy]oxo-                                                              acetic acid ethyl ester                         24 H  OC.sub.6 H.sub.5                                                                   H    OH   H    H   [(4-oxo-3-phenoxy-2,5,7-cycloheptatrien-1-yl                                  )oxy]oxo-                                                                     acetic acid ethyl ester                         25 H  N(C.sub.4 H.sub.9).sub.2                                                           H    I    OH   H   [(5-dibutylamino-3-oxo-1,4,6-cycloheptatrien                                  -1-yl)oxy]oxo-                                                                acetic acid methyl ester                        26 CH.sub.3                                                                         H    OH   CH.sub.3                                                                           H    C.sub.6 H.sub.13                                                                  [(3,7-dimethyl-5-hexyl-2,5,7-cycloheptatrien                                  -1-yl)oxy]oxo-                                                                acetic acid methyl ester                        27 Cl H    H    OH   H    OH  [(5-chloro-4-oxo-2,5,7-cycloheptatrien-1,3-d                                  iyl)bis(oxy)]-                                                                bis[2-oxo-acetic acid]diethyl ester             28 H  OH   Br   H    OC.sub.3 H.sub.7                                                                   H   [(7-bromo-3-oxo-5-phenoxy-1,4,6-cycloheptatr                                  ien-1-yl)oxy]oxo-                                                             acetic acid ethyl ester                         29 OH H    CH(CH.sub.3)                                                                       H    C.sub.2 H.sub.5                                                                    H   [[4-ethyl-6-(1-methylbutyl)2-oxo-3,5,7-cyclo                                  heptatrien-1-                                              C.sub.3 H.sub.7    yl]oxy]oxo-acetic acid ethyl ester              30 H  C.sub.6 H.sub. 5                                                                   OH   H    N(CH.sub.3).sub.2                                                                  H   [(6-dimethylamino-4-oxo-2-phenyl-4-oxo-2,5,7                                  -cycloheptatrien-                                                             1-yl)oxy]oxo-acetic acid ethyl ester            31 H  CF.sub.3                                                                           H    OC.sub.4 H.sub.9                                                                   H    OH  [(6-butoxy-2-oxo-4-trifluoromethyl-3,5,7-cyc                                  loheptatrien-1-                                                               yl)oxy]oxo-acetic acid methyl ester                                           -32 OH H H OH H OH [(2-oxo-3,5,7-cycloheptat                                  riene-1,3,5-triyl)tris(oxy)]tris[2-                                           oxo-acetic acid]trimethyl ester                 33 H  N(C.sub.3 H.sub.7).sub.2                                                           H    C.sub.2 H.sub.5                                                                    H    OH  [(4-dipropylamino-6-ethyl-2-oxo-3,5,7-cycloh                                  eptatrien-1-                                                                  yl)oxy]oxo-acetic acid ethyl ester              34 CH.sub.3                                                                         CH.sub.3                                                                           OH   H    H    C.sub.2 H.sub.5                                                                   [(2,3-dimethyl-5-ethyl-4-oxo-2,5,7-cyclohept                                  atrien-1-yl)-                                                                 oxy]oxo-acetic acid methyl ester                35 C.sub.6 H.sub.5                                                                  OCH.sub.3                                                                          H    OH   H    CF.sub.3                                                                          [(6-methoxy-4-oxo-5-phenyl-3-trifluoromethyl                                  -2,5,7-cyclo-                                                                 heptatrien-1-yl)oxy]oxo-acetic acid ethyl                                     ester                                           36 H  H    C.sub.5 H.sub.11                                                                   OCH.sub.2 C                                                                        OH   H   [[7-(2-methylpropyloxy)-3-oxo-6-pentyl-1,4,6                                  -cycloheptatrien-                                               (CH.sub.3).sub.2                                                                            1-yl]oxy]oxo-acetic acid ethyl ester            37 H  H    OH   H    H    OH  [(2-oxo-3,5,7-cycloheptatriene-1,5-diyl)bis(                                  oxy)]bis[2-oxo-                                                               acetic acid]diethyl ester                       38 OH H    CF.sub.3                                                                           H    OC.sub.6 H.sub.5                                                                   H   [(4-phenoxy-2-oxo-6-trifluoromethyl-3,5,7-cy                                  cloheptatrien-                                                                1-yl)oxy]oxo-acetic acid methyl ester           39 H  OH   H    Br   N(CH.sub.3).sub.2                                                                  H   [(6-bromo-5-dimethylamino-3-oxo-1,4,6-cycloh                                  eptatrien-                                                                    1-yl)oxy]oxo-acetic acid methyl                 __________________________________________________________________________                                  ester                                       

EXAMPLE 40 [(2-Oxo-3,5,7-cycloheptatrien-1-yl)thio]acetic Acid MethylEster IV (R¹⁹ =S--CH₂ --COOCH₃ ; R²⁰, R²¹, R²², R²³ and R²⁴ =H)

A solution of the compound of formula IV, methyl mercaptoacetate (4.12ml), in methylene chloride (40 ml) is added dropwise to a solution ofthe compound of formula II, 2-chloro-2,4,6-cycloheptatrien-1-one [5.6 g,described by T. Nozoe et al., Proc. Japan. Acad., 28, 483 (1952)], andtriethylamine (6.12 ml) in methylene chloride (60 ml). After completionof the addition, the mixture is stirred at room temperature for 30minutes. Methylene chloride is added and the solution is treated withcharcoal and filtered. The filtrate is evaporated and the residue iscrystallized from chloroformhexane to give the title compound, mp71°-72° C.

In the same manner but replacing 2-chloro-2,4,6-cycloheptatrien-1-onewith an equivalent amount of4-bromo-7-methyl-2-phenoxy-2,4,6-cycloheptatrien-1-one,6-chloro-2-hydoxy-4-diethylamino or5-bromo-7-butyl-3-phenyl-2,4,6-cycloheptatrien-1-one, the correspondingcompounds of formula IV[(5-oxo-4-phenoxy-6-methyl-1,3,6-cycloheptatrien-1-yl)thio]acetic acidmethyl ester,[(3-diethylamino-5-hydroxy-6-oxo-2,4,7-cycloheptatrien-1-yl)thio]aceticacid methyl ester and[(3-butyl-4-oxo-6-phenyl-2,4,7-cycloheptatrien-1-yl)thio]acetic acidmethyl ester are obtained respectively.

EXAMPLE 41 [(2-Oxo-3,5,7-cycloheptatrien-1-yl)sulfino]acetic Acid MethylEster I (R¹ =SO--CH₂ --COOCH₃ ; R², R³, R⁴, R⁵ and R⁶ =H)

A solution of [(2-oxo-3,5,7-cycloheptatrien-1-yl)thio]acetic acid methylester (2.1 g, described in Example 40) in chloroform (15 ml) is addeddropwise to a solution of 0° C. of m-chloroperbenzoic acid (2.8 g) inchloroform (20 ml). The mixture is stirred at 0° C. for 30 minutes andfiltered. The filtrate is diluted with chloroform, washed with sodiumbicarbonate solution and water, dried and evaporated. The residue isdissolved in ether-chloroform and filtered. The filtrate is evaporatedand the residue is crystallized from chloroform-hexane to give the titlecompound, mp 101° C.

In the same manner but replacing m-chloroperbenzoic acid with anequivalent amount of perbenzoic acid the title compound is obtained.

In the same manner but replacing[(2-oxo-3,5,7-cycloheptatrien-1-yl)thio]acetic acid methyl ester with anequivalent amount of[(5-oxo-4-phenoxy-6-methyl-1,3,6-cycloheptatrien-1-yl)thio]acetic acidmethyl ester,[(3-diethylamino-5-hydroxy-6-oxo-2,4,7-cycloheptatrien-1-yl)thio]aceticacid methyl ester or[(3-butyl-4-oxo-6-phenyl-2,5,7-cycloheptatrien-1-yl)thio]acetic acidmethyl ester, described in Example 40,[(5-oxo-4-phenoxy-6-methyl-1,3,6-cycloheptatrien-1-yl)sulfino]-aceticacid methyl ester,[(3-diethylamino-5-hydroxy-6-oxo-2,4,7-cycloheptatrien-1-yl)sulfino]-aceticacid ethyl ester and[(3-butyl-4-oxo-6-phenyl-2,5,7-cyclohpetatrien-1-yl)sulfino]-acetic acidmethyl ester are obtained respectively.

EXAMPLE 42 [(2-Oxo-3,5,7-cycloheptatrien-1-yl)sulfono]acetic acid MethylEster I (R¹ =SO₂ --CH₂ --COOCH₃ ; R², R³, R⁴, R⁵ and R⁶ =H)

A solution of [(2-oxo-3,5,7-cycloheptatrien-1-yl)thio]acetic acid methylester (1.75 g, described in Example 40) in chloroform (10 ml) is addeddropwise to a solution at 0° C. of m-chloroperbenzoic acid (2.3 g) inchloroform (15 ml). The mixture is stirred at 0° C. for 5 minutes.m-Chlorobenzoic acid (2.3 g) is added and the reaction mixture is heatedat 50° C. for one hour. The solution is diluted with chloroform, washedwith sodium bicarbonate solution and water, dried and evaporated. Theresidue is crystallized from chloroformhexane to give the titlecompound, mp 117°-118° C.

In the same manner but replacing m-chlorobenzoic acid with an equivalentamount of perbenzoic acid the title compound is obtained.

In the same manner but replacing[(2-oxo-3,5,7-cycloheptatrien-1-yl)thio]acetic acid methyl ester with anequivalent amount of[(5-oxo-4-phenoxy-6-methyl-1,3,6-cycloheptatrien-1-yl)thio]acetic acidmethyl ester,[(3-diethylamino-5-hydroxy-6-oxo-2,4,7-cycloheptatrien-1-yl)thio]aceticacid methyl ester or[(3-butyl-4-oxo-6-phenyl-2,5,7-cycloheptatrien-1-yl)thio]acetic acidmethyl ester, described in Example 40[(5-oxo-4-phenoxy-6-methyl-1,3,6-cycloheptatrien-1-yl)sulfono]-aceticacid methyl ester,[(3-diethylamino-5-hydroxy-6-oxo-2,4,7-cycloheptatrien-1-yl)sulfono]-aceticacid methyl ester and[(3-butyl-4-oxo-6-phenyl-2,5,7-cycloheptatrien-1-yl)sulfono]-acetic acidmethyl ester are obtained respectively.

We claim:
 1. A compound of formula 1 ##STR5## in which R¹, R², R³, R⁴,R⁵ and R⁶ are the same or different selected from the group consistingof hydrogen; halo, trifluoromethyl; lower alkoxy, lower alkyl; phenyl;hydroxy; phenoxy; mercapto; NR⁷ R⁸ wherein each of R⁷ and R⁸ is hydrogenor lower alkyl; and a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Yis 0, R⁹ and R¹⁰ together are oxo and R¹¹ is hydrogen or lower alkyl,;with the proviso that one, two or three of R¹, R², R³, R⁴, R⁵ and R⁶must be a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y, R⁹, R¹⁰ andR¹¹ are as defined in each instance herein: or a therapeuticallyacceptable salt thereof.
 2. A compound of formula 1 ##STR6## in whichR¹, R², R³, R⁴, R⁵ and R⁶ are the same or different selected from thegroup consisting of hydrogen or a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹wherein Y is 0, R⁹ and R¹⁰ together are oxo and R¹¹ is hydrogen or loweralkyl, with the proviso that one, two or three of R¹, R², R³, R⁴, R⁵ andR⁶ must be a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y, R⁹, R¹⁰and R¹¹ are as defined in each instance herein; or a therapeuticallyacceptable salt thereof.
 3. A compound of formula 1 ##STR7## in which(a) R¹ is a radical of formula Y--CR⁹ R¹⁰ --COOR¹¹ wherein Y is 0, R⁹and R¹⁰ together are oxo and R¹¹ is hydrogen or lower alkyl and R², R³,R⁴, R⁵ and R⁶ are hydrogen; ora therapeutically acceptable salt thereof.4. [(2-Oxo-3,5,7-cycloheptatrien-1-yl)oxy]oxo-acetic acid ethyl ester,as claimed in claim
 1. 5. A method for suppressing allergicmanifestations of anaphylactic reactions and atopic hypersensitivity ina mammal which comprises administering to said mammal an effectiveamount of a compound of claim 1, or a therapeutically acceptable saltthereof.
 6. A pharmaceutical composition useful in suppressing allergicmanifestations of anaphylactic reactions and atopic hypersensitivitycomprising a compound of claim 1, or a therapeutically acceptable saltthereof, and a pharmaceutically acceptable carrier.